Optimization of aminolevulinic acid-protoporphyrin IX for fluorescence-guided tumor resection and treatment

The long-term goal of our research is to determine tumor phenotypic and genotypic characteristics that reduce
tumor protoporphyrin IX fluorescence and design mechanism-based approaches to overcome these limiting
factors – this first renewal builds on progress made in our initial funding period. Surgery is the most common
treatment for all types of solid tumors. A successful cancer surgery is to completely remove tumor tissues and
maximally preserve normal structures. To improve cancer surgery accuracy and precision, fluorescent molecular
probes have been developed and are being increasingly used in the oncological surgery. Fluorescence from
intraoperative molecular probes enables surgeons to visualize tumor tissues in real time and perform
fluorescence-guided resection (FGR). It has been well demonstrated that FGR leads to more complete tumor
resection and better surgical outcomes than conventional surgery under white light. Aminolevulinic acid (ALA) is
one of a few FDA-approved intraoperative fluorescent probes and the only molecular probe based on the
metabolic alterations in tumor cells. ALA has no fluorescence on its own and needs to be metabolized in the
heme biosynthesis pathway in tumor cells to produce a fluorescent and photosensitizing metabolite
protoporphyrin IX (PpIX), which enables tumor fluorescence imaging and photodynamic therapy (PDT). Although
ALA-PpIX has been clinically used for tumor FGR, its applications are limited by low tumor PpIX fluorescence,
high tumor fluorescence heterogeneity, and low tumor-to-normal tissue fluorescence contrast. Studies in the
initial funding period of this award have led to the identification of ABCG2 transporter activity as a critical factor
in reducing tumor PpIX fluorescence. Importantly, we have identified clinically used agents to suppress ABCG2
activity to enhance tumor PpIX fluorescence. In this renewal, we will use an FDA-approved drug lapatinib (Lap),
the most potent one we have identified for the enhancement of tumor PpIX fluorescence, and hypothesize that
lapatinib improves the use of ALA for FGR and PDT of gliomas. We chose to study this enhancement strategy
in gliomas because ALA is now primarily used for guiding the resection of gliomas and, more importantly, ABCG2
expression elevation is a common feature in human gliomas. To this end, we will evaluate Lap in combination
with ALA for the enhancement of PpIX fluorescence and PDT response in human glioma cell lines with different
genotype and phenotype (Aim 1) and glioma tumor models (Aim 2). Through this research, we hope to
demonstrate that Lap in combination with ALA enhances tumor PpIX fluorescence and PDT response. The
successful completion of this research will lead to an optimized use of ALA for FGR and PDT treatment of
gliomas.

Grant Number: 6R15CA268200-03
NIH Institute/Center: NIH
Principal Investigator: BIN CHEN